The Skeleton
The skeleton is a complex organ system that is in a constant state of flux. It serves mechanical, metabolic, and protective functions. There are two types of bone; cortical and cancellous. Cortical bone is found primarily in the shafts of the long bones of the appendicular skeleton. It is also found in the outer layer of virtually all bones. Cancellous bone is found primarily in the bones of the axial skeleton and in the ends of the long bones. The cellular process of bone activity through which both cortical and cancellous bone are maintained, is referred to as bone remodelling. This remodelling takes place on bone surfaces in discrete packets known as basic multicellular units (Parfitt et al., (1987) Clin. Obstet. Gynecol. 30:786-811).
There are numerous systemic hormones, such as parathyroid hormone and vitamins such as vitamin D, calcitonin, estrogens, androgens, as well as a number of local factors, such as interleukins, transforming growth factors and prostaglandins, that play an important role in the physiology of bone remodelling.
Skeletal Disorders
Many factors contribute to the strength of the skeleton and its ability to withstand trauma without fracture. The major factor accounting for at least 70% of bone strength is bone mineral density (mass per volume). Approximately 80% of the total skeletal mass is cortical (compact) bone with a low surface: volume ratio while remaining 20% is cancellous (spongy) bone with a much higher surface: volume ratio. Alterations in the interrelationship between mass, volume, surface, and architecture are all considered in the loss of bone strength. Such a loss in bone strength will lead to an increased risk of fracture, which is one of the hallmarks of osteoporosis.
Skeletal disorders lead to a loss or weakening in bones, a condition generally termed osteoporosis.
Osteoporosis
Osteoporosis is a condition with decreased bone mass and changes in the microarchitecture of the bone, which leads to decreased strength and an increased risk for fracture.
Osteoporosis is one of the few medical conditions that affects virtually every member of the human species living beyond the age of 35. It is a major medical problem with rising medical, social, and economical consequences. Over 8 million Americans suffer from osteoporotic fractures, although the number of affected individuals is estimated to 14-25 millions using newer definitions of osteoporosis, which include those who have not yet experienced fractures but have sufficiently low bone mass to place them in potential risk groups.
The National Osteoporosis Foundation, USA, has given estimates that the cost of treating osteoporosis in 1990 was $10 billion. With the aging of the population and the increasing prevalence of osteoporosis, medical costs alone is predicted to reach $30-45 billion before the year 2020 in the USA only. The World Health Organisation has proclaimed the decade 2000-2010 as the Decade of Bone and Joint Diseases.
Current therapies for treatment of osteoporosis usually acts by a mechanism of increased formation or decreased resorbtion of bone material. The effects of such treatments are summarised in table 1. Other proposed means of treating osteoporosis include calcium, exercise, and growth hormones.
TABLE 1Common osteoporosis therapy strategiesStrategyDecrease resoptionIncrease formationEffect on bone massStabilizeIncreaseEffect on bone cellsDecrease osteoclastIncrease osteoblast activityactivityExamplesEstrogen, calcitonin,Fluoride, Vitamin D,bisphosphonatesparathyroid hormone(PTH)Medical Causes of Osteoporosis
Different medical disorders may, as a secondary effect, also lead to osteoporosis. Such medical disorders are listed in Table 2.
TABLE 2Different medical disorders causing osteoporosisRenalRenal failureIdiopathic hypercalciuriaRenal tubular acidosisEndocrine/metabolicDiabetes mellitus type ICushing's syndromeHypogonadism - primary and secondaryHyperparathyroidism -primary and secondaryHyperthyroidismHomocystinuriaAcromegalyHypovitaminosis DScurvyHematologic/oncologicLeukemiaLymphomaMultiple myelomaWaldenstrom's macroglobulinemiaSystemic mastocytosisHemolytic anemiasSickle cell diseaseBeta-thalassemiaPTHrP-secreting solidtumors (esp. squamous)renal, bladder, ovarian)GastrointestinalInflammatory bowel diseaseGluten enteropathyPostgastrectomyPrimary biliary cirrhosisHepatic insufficiencyHemochromatosisWilson's diseaseMalnutritionChronic inflammatory diseasesRheumatoid arthritisPharmacologic agentsAluminium-containing antacidsAnticonvulsantsCisplatinCyclosporineGlucocorticoidsHeparinMethotrexatePlicamycinThyroid hormone excessDiuretics except thiazidesAlcoholOtherImmobilizationOsteogenesis imperfectaDisuse/paralysisEhlers-Danlos syndromeMarfans syndromePost organ transplantationPregnancyGaucher's diseasePostmenopausal Bone Loss
The last decade, the significance and consequence of postmenopausal bone loss have been identified and defined at an international level. Medical and governmental authorities have recognised the morbidity and mortality in untreated individuals as well as the financial consequence to the society.
Known Treatment of Osteoporosis
Few drugs are currently known to increase bone formation. The most commonly used and studied drug is fluoride, being able to affect both bone formation and resorption. The drug is thus widely used in modem fluorotherapy (Farley et al., Science, 222:330-332, (1983), and Gruber et al., Clin. Orthop., 267:264-267), and sodium fluoride is the most evaluated form.
Several studies show an increase in trabecular bone mass after long-term administration of fluoride and calcium. The combination of fluoride and calcium is considered as an established treatment.
Fluoride based drugs, where monofluorophospate represents the most advanced drug for fluorotherapy, show several drawbacks and often lead to complications in treated patients, e.g. gastrointestinal and rheumatic complications.
Affinito et al. have in (Gynecol. Endocrinol. (7:201-205, (1993)) published a study showing an increase of 4.25% in bone mineral density after treatment of postmenopausal women with yet another form of a fluoride based drug, i.e. L-glutamine calcium monofluorophospate.
Bone Problems in Birds
In chickens, hens and other broilers, such as turkeys, the weight-carrying capacity of the legs is a problem. Specifically, in several lines of turkeys gaining a body weight of more than 25 kilos bone fracture is a problem. To prevent such problems that cause unnecessary suffering of the animal as well as high costs for the farmer, there is a needs for better understanding of bone growth, bone formation and bone mineralisation.
Prophylaxis
Recent trends in the prophylaxis of the skeletal diseases demand better understanding of physiological processes of the bone formation, development and mineralization during the postnatal life of a vertebrate, including mammal and bird.
Developmental Concerns of the Skeleton
The delivery, and the consecutive hours after, are the main source of stimuli which activate functions of the digestive system, respiratory system and motion system as a function of the gravitation and dynamic load on limb bones. Additionally, there is a differentiation during the development regarding bone mass gain, muscular mass gain and fat mass gain at various stages of life.
General nutritional status, specific nutrients (e.g., zinc, glutamine), and certain tropic growth factors (e.g., growth hormone, insulin-like growth factor I, keratinocyte growth factor, and glucagon-like peptide-2) have important interactions relevant for intestinal growth and function, which, in turn, affect the development of the limb. Adequate nutritional status is critical for endogenous growth factor synthesis in the gut and other tissues and is an important mediator of organ responsiveness to exogenous growth factor administration.
It is thus highly desirable in the light of the aforementioned problems to develop means and methods for treating or preventing any condition associated with bone loss or weakening, which can also avoid problems associated with prior art means and methods. In this respect, the present invention addresses this need and interest.